EP3097094A1 - Fluor-naphthyl-derivate - Google Patents
Fluor-naphthyl-derivateInfo
- Publication number
- EP3097094A1 EP3097094A1 EP15702398.7A EP15702398A EP3097094A1 EP 3097094 A1 EP3097094 A1 EP 3097094A1 EP 15702398 A EP15702398 A EP 15702398A EP 3097094 A1 EP3097094 A1 EP 3097094A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- fluoro
- methyl
- naphthamide
- compound
- pyran
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- -1 Fluoro-naphthyl Chemical class 0.000 title claims description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 98
- 239000000203 mixture Substances 0.000 claims abstract description 44
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 21
- 201000000980 schizophrenia Diseases 0.000 claims abstract description 16
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 15
- 238000011282 treatment Methods 0.000 claims abstract description 15
- 239000002253 acid Substances 0.000 claims abstract description 12
- 125000001424 substituent group Chemical group 0.000 claims abstract description 11
- 208000028698 Cognitive impairment Diseases 0.000 claims abstract description 9
- 208000010877 cognitive disease Diseases 0.000 claims abstract description 9
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 9
- 150000002367 halogens Chemical group 0.000 claims abstract description 9
- 208000027520 Somatoform disease Diseases 0.000 claims abstract description 8
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 8
- 208000027753 pain disease Diseases 0.000 claims abstract description 8
- 208000019116 sleep disease Diseases 0.000 claims abstract description 8
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 5
- 239000001257 hydrogen Substances 0.000 claims abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 5
- 125000003386 piperidinyl group Chemical group 0.000 claims abstract description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 3
- 230000003287 optical effect Effects 0.000 claims abstract description 3
- 238000011321 prophylaxis Methods 0.000 claims abstract 4
- 238000000034 method Methods 0.000 claims description 18
- 230000008569 process Effects 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- JVXXKQIRGQDWOJ-UHFFFAOYSA-N naphthalene-2-carboxamide Chemical compound C1=CC=CC2=CC(C(=O)N)=CC=C21 JVXXKQIRGQDWOJ-UHFFFAOYSA-N 0.000 claims description 5
- VMJJGOKGXBMAEQ-DQEYMECFSA-N 4-[(4-cyano-4-pyridin-2-ylpiperidin-1-yl)methyl]-1-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]naphthalene-2-carboxamide Chemical compound C(#N)C1(CCN(CC1)CC1=CC(=C(C2=CC=CC=C12)F)C(=O)N[C@@H]1[C@H](CCCC1)O)C1=NC=CC=C1 VMJJGOKGXBMAEQ-DQEYMECFSA-N 0.000 claims description 4
- 239000013543 active substance Substances 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 230000001225 therapeutic effect Effects 0.000 claims description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 4
- 230000003213 activating effect Effects 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 3
- JEEWUVRTVKDADJ-UHFFFAOYSA-N 4-[(4-cyanophenyl)methyl]-1-fluoro-N-(3-hydroxyoxan-4-yl)naphthalene-2-carboxamide Chemical compound C(#N)C1=CC=C(CC2=CC(=C(C3=CC=CC=C23)F)C(=O)NC2C(COCC2)O)C=C1 JEEWUVRTVKDADJ-UHFFFAOYSA-N 0.000 claims description 2
- OCZBYPSETUGCDU-OALUTQOASA-N 4-[(6-chloropyridin-3-yl)methyl]-1-fluoro-N-[(3S,4S)-4-hydroxyoxan-3-yl]naphthalene-2-carboxamide Chemical compound ClC1=CC=C(C=N1)CC1=CC(=C(C2=CC=CC=C12)F)C(=O)N[C@H]1COCC[C@@H]1O OCZBYPSETUGCDU-OALUTQOASA-N 0.000 claims description 2
- NZMSZBWQPZHKMS-SFTDATJTSA-N 1-fluoro-N-[(3R,4S)-3-hydroxyoxan-4-yl]-4-[[4-(trifluoromethoxy)phenyl]methyl]naphthalene-2-carboxamide Chemical compound O[C@H]1COCC[C@@H]1NC(=O)C1=C(F)C2=CC=CC=C2C(CC2=CC=C(OC(F)(F)F)C=C2)=C1 NZMSZBWQPZHKMS-SFTDATJTSA-N 0.000 claims 1
- FVLBGBMUWXGDJP-UHFFFAOYSA-N 4-benzyl-1-fluoro-N-(3-hydroxyoxan-4-yl)naphthalene-2-carboxamide 4-[(4-chlorophenyl)methyl]-1-fluoro-N-(3-hydroxyoxan-4-yl)naphthalene-2-carboxamide Chemical compound OC1COCCC1NC(=O)c1cc(Cc2ccccc2)c2ccccc2c1F.OC1COCCC1NC(=O)c1cc(Cc2ccc(Cl)cc2)c2ccccc2c1F FVLBGBMUWXGDJP-UHFFFAOYSA-N 0.000 claims 1
- IJEYAFXCWKUYBT-IXPQBOJDSA-N ClC1=CC=C(C=N1)CC1=CC(=C(C2=CC=CC=C12)F)C(=O)N[C@@H]1[C@@H](CCC1)O.ClC1=CC=C(C=N1)CC1=CC(=C(C2=CC=CC=C12)F)C(=O)N[C@@H]1[C@H](CCC1)O Chemical compound ClC1=CC=C(C=N1)CC1=CC(=C(C2=CC=CC=C12)F)C(=O)N[C@@H]1[C@@H](CCC1)O.ClC1=CC=C(C=N1)CC1=CC(=C(C2=CC=CC=C12)F)C(=O)N[C@@H]1[C@H](CCC1)O IJEYAFXCWKUYBT-IXPQBOJDSA-N 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 75
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- 235000019439 ethyl acetate Nutrition 0.000 description 32
- 239000000243 solution Substances 0.000 description 32
- 239000007787 solid Substances 0.000 description 27
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 102000005962 receptors Human genes 0.000 description 18
- 108020003175 receptors Proteins 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 17
- 230000000694 effects Effects 0.000 description 17
- 239000011734 sodium Substances 0.000 description 17
- 239000010410 layer Substances 0.000 description 15
- 239000012043 crude product Substances 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 11
- 238000010898 silica gel chromatography Methods 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 239000003480 eluent Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 230000003551 muscarinic effect Effects 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 8
- 229960004373 acetylcholine Drugs 0.000 description 8
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 210000004556 brain Anatomy 0.000 description 7
- 239000000969 carrier Substances 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 description 6
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 description 6
- 239000000556 agonist Substances 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- RMHJJUOPOWPRBP-UHFFFAOYSA-N naphthalene-1-carboxamide Chemical compound C1=CC=C2C(C(=O)N)=CC=CC2=C1 RMHJJUOPOWPRBP-UHFFFAOYSA-N 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 230000004913 activation Effects 0.000 description 5
- 230000003281 allosteric effect Effects 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 210000001320 hippocampus Anatomy 0.000 description 5
- 229920002401 polyacrylamide Polymers 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 229940062627 tribasic potassium phosphate Drugs 0.000 description 5
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 5
- 229940086542 triethylamine Drugs 0.000 description 5
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- BRLKZNNEDKVYAT-UHFFFAOYSA-N 4-bromo-1-fluoronaphthalene-2-carboxylic acid Chemical compound BrC1=CC(=C(C2=CC=CC=C12)F)C(=O)O BRLKZNNEDKVYAT-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 229960003638 dopamine Drugs 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 238000002955 isolation Methods 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 210000001577 neostriatum Anatomy 0.000 description 4
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- 229920005862 polyol Polymers 0.000 description 4
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- 238000012545 processing Methods 0.000 description 4
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- 229920006395 saturated elastomer Polymers 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- ODFVXVSVXQOSMG-PMACEKPBSA-N 4-[(6-chloropyridin-3-yl)methyl]-1-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]naphthalene-2-carboxamide Chemical compound ClC1=CC=C(C=N1)CC1=CC(=C(C2=CC=CC=C12)F)C(=O)N[C@@H]1[C@H](CCCC1)O ODFVXVSVXQOSMG-PMACEKPBSA-N 0.000 description 3
- QJBWZDXHWCSCMB-UHFFFAOYSA-N 4-[(6-chloropyridin-3-yl)methyl]-1-fluoronaphthalene-2-carboxylic acid Chemical compound ClC1=CC=C(C=N1)CC1=CC(=C(C2=CC=CC=C12)F)C(=O)O QJBWZDXHWCSCMB-UHFFFAOYSA-N 0.000 description 3
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- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000012981 Hank's balanced salt solution Substances 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
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- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-tetramethylpiperidine Chemical compound CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 description 2
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- PQSXTBMHLNJQKD-UHFFFAOYSA-M 2-chloro-5-methanidylpyridine;chlorozinc(1+) Chemical compound [Zn+]Cl.[CH2-]C1=CC=C(Cl)N=C1 PQSXTBMHLNJQKD-UHFFFAOYSA-M 0.000 description 2
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- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
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- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
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- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A—HUMAN NECESSITIES
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- A61P25/20—Hypnotics; Sedatives
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/56—Amides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/14—Nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- R 1 is C 4 _6-cycloalkyl or C 4 _6-heterocycloalkyl, which are optionally substituted by one or two substituents, selected from hydroxy or lower alkyl;
- A is phenyl, pyridinyl or piperidinyl
- R is hydrogen, halogen, lower alkyl, cyano, C 4 _6-cycloalkyl, lower alkoxy, lower alkoxy substituted by halogen, or is a five-or six-membered heteroaryl group, optionally substituted by lower alkyl; n is 1 or 2;
- WO 2011149801 describes similar compounds for treating neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction.
- the activity (EC 50 in nM) is about 2 or more times lower, and therefore these compounds are less suitable for the development of corresponding drugs.
- the F- substitution on the naphthyl ring instead of OR 1 in WO 2011149801 leads to more active compounds, which could not predicted.
- the compounds of the present invention are muscarinic Ml receptor positive allosteric modulators (PAM) and hence are useful in the treatment of diseases, mediated by the muscarinic Ml receptor, such as Alzheimer's disease, cognitive impairment, schizophrenia,
- PAM muscarinic Ml receptor positive allosteric modulators
- Acetylcholine is a neurotransmitter which activates both nicotinic (ligand-gated ion channel) and muscarinic (metabotropic) receptors in the CNS and in the periphery.
- the muscarinic receptors are members of the class A G-protein-coupled receptors. To date, five distinct subtypes of mAChRs (M1-M5) have been cloned and sequenced. The muscarinic Ml receptors are predominantly distributed in the brain, with the highest expression in the cortex, thalamus, striatum and hippocampus. In clinical studies, Xanomeline, a Ml/M4-preferring agonist, demonstrated robust efficacy on positive, negative and cognitive symptoms in schizophrenic patients and improved cognitive scores and reduced psychotic-like behaviors in patients with Alzheimer's disease (AD). The Ml receptor has been implicated in memory and learning processes, regulation of dopamine and NMD A receptor activity and has thus been proposed as a potential target for the treatment of AD and schizophrenia.
- AD Alzheimer's disease
- AD Alzheimer's disease
- Pathologically AD is characterized by the deposition in the brain of amyloid in extracellular plaques and intracellular neurofibrillary tangles.
- the amyloid plaques are mainly composed of amyloid peptides (Abeta peptides) which originate from the ⁇ -Amyloid Precursor Protein (APP) by a series of proteolytic cleavage steps.
- APP ⁇ -Amyloid Precursor Protein
- the Abeta peptides are derived from the same domain of the APP but differ at their N- and C-termini, the main species are of 40 and 42 amino-acid length by processing of the beta-amyloid precursor protein (APP) by the beta- amyloid protein cleaving enzyme. The processing leads to accumulation of Abeta in the brain.
- APP beta-amyloid precursor protein
- Ml receptors are abundantly expressed postsynaptically in cortex, hippocampus and striatum which are important brain regions involved for cognition. Based on the cholinergic hypothesis i.e. degeneration of presynaptic cholinergic nerve terminals in hippocampus and cortical regions, Ml activation should rescue the cognitive deficits which occur in AD, thus providing symptomatic treatment of this neurodegenerative disorder. Postmortem studies in AD cortical tissues have shown that Ml receptor expression are not reduced, thus providing evidence for target availability in a critical brain region.
- Ml activation has potential as a disease-modifying therapy for AD by shifting the APP processing towards the non-amyloidogenic a-secretase pathway and by decreasing tau hyperphosphorylation. Therefore, Ml PAMs provide an approach to target both symptomatic and disease-modifying treatment of AD.
- Schizophrenia is a severe, disabling, lifelong disorder that affects 1% of the population and is characterized by positive symptoms (such as hallucinations, delusions and paranoia), negative symptoms (such as social withdrawal and apathy) and cognitive impairment (for example, deficits in working memory, executive function and attention). Schizophrenia is a neurodevelopmental disorder with genetic risk factors and neuropathological changes.
- NMDA receptor function in pyramidal neurons coupled with sub-optimal dopamine release in critical regions such as dorsolateral prefrontal cortex may account for some of the cognitive deficits.
- Ml receptors are located in regions which are affected in schizophrenia, such as the hippocampus, cortex and striatum, in particular in the medium spiny neurons.
- Several reports have shown a reduction in muscarinic receptors in the prefrontal cortex and hippocampus, regions where Ml is densely expressed, in a subset of schizophrenic patients.
- preclinical studies have shown that Ml knockout mice have enhanced amphetamine-induced activity and increased striatal dopamine levels. Electrophysiology studies have revealed that activation of Ml receptors potentiates NMDA mediated hippocampal activity, modulates activity of medium spiny neurons and increases activity of medial prefrontal cortex neurons. Overall, activation of Ml receptors should modulate dysfunctional dopaminergic and glutamatergic signaling within the underlying neurocircuitry resulting in improvements in the symptoms of schizophrenia.
- an alternative approach consists of developing Ml PAMs that act at the less highly conserved allosteric binding sites.
- M I PAMs from different chemical classes exhibiting, as rationalized, a good level of M I subtype selectivity.
- these M 1 allosteric agents demonstrated pro-cognitive effects (in scopolamine-induced memory deficit in mice, scopolamine impaired non-human primates and in transgenic AD mice).
- PQCA and ML 169 have been shown to promote non-am y I oidogen ic APP processing.
- Electrophysiology studies have shown that Ml PAMs potentiate carbachol-induced activity in the medial prefrontal corte and medium spiny neurons.
- M 1 PAMs do not appear to produce side effects such as salivation at therapeutic effective doses. Additionally, they are expected to be devoid of liabilities such as receptor
- the PA M approach by activating in a truly selective manner M 1 receptors, is a highly promising novel strategy to deliver both efficacious and safe therapeutic agents for the treatment of schizophrenia (positive, negative and cognitive symptoms) as well as AD (symptomatic and disease modifyin ).
- the compounds of the invention which are muscarinic Ml receptor positive allosteric modulators, are believed to be useful in the treatment of Alzheimer's disease and other diseases mediated by the muscarinic Ml receptor, without side effects.
- the object of the present invention was to identify compounds that are muscarinic Ml receptor positive allosteric modulators. It has been found that the compounds of formula I are active in this area and they may therefore be used for the treatment of Alzheimer's disease, cognitive impairment, schizophrenia, pain or sleep disorders
- the present invention relates to compounds of formula I and to their pharmaceutically acceptable salts, to these compounds as pharmaceutically active substances, to the processes for their production, as well as to the use in the treatment or prevention of disorders, relating to muscarinic Ml receptor positive allosteric modulators, and to pharmaceutical compositions containing the compounds of formula I.
- the following definitions of the general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination.
- lower alkyl denotes a saturated, i.e. aliphatic hydrocarbon group including a straight or branched carbon chain with 1 - 7 carbon atoms.
- alkyl examples are methyl, ethyl, n-propyl, isopropyl, n- butyl, i-butyl, 2-butyl, t-butyl and the like.
- C 4 _6-cycloalkyl denotes a saturated carbon ring, containing from 4 to 6 carbon ring atoms, for example cyclobutyl, cyclopentyl or cyclohexyl.
- alkoxy denotes a group -O-R' wherein R' is lower alkyl as defined above.
- halogen denotes chlorine, bromine, fluorine or iodine.
- lower alkoxy substituted by halogen denotes an alkyl group as defined above, wherein at least one hydrogen atoms is replaced by halogen, for example OCF 3 , OCH 2 F, OCH 2 CF3, OCH 2 CH 2 CF3, OCH 2 CF 2 CF3 and the like.
- C 4 _6-heterocycloalkyl denotes a non aromatic heterocyclic ring with 4 to 6 ring atoms, containing at least one O atom, for example tetrahydropyran-4-yl, tetrahydropyran-3-yl, oxolan-3-yl, oxetan-3-yl, oxetan-2-yl or tetrahydrofuran-2-yl.
- five or six-membered heteroaryl denotes aromatic rings with 5 or 6 ring atoms, containing at least one N, S or O atom, for example pyrazolyl, imidazolyl, 1,2,4- triazolyl, thiazolyl, 1,2,4-oxadiazolyl or pyridinyl.
- pharmaceutically acceptable salt or “pharmaceutically acceptable acid addition salt” embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane- sulfonic acid, p-toluenesulfonic acid and the like
- One embodiment of the present invention are compounds of formula I, wherein A is phenyl and the other substituents are as described above, for example the following compounds:
- One further embodiment of the present invention are compounds of formula I, wherein A is pyridinyl and the other substituents are as described above, for example the following compounds:
- One embodiment of the invention are further compounds of formula I, wherein A is piperidinyl and the other substituents are as described above, for example the following compound
- an activating agent such as BOP (Benzotriazol-1- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate or thionyl chloride to a compound of formula
- the compounds of formula I may be prepared in accordance with process variant a) and with the following schemes 1 and 2.
- Starting materials are commercially available, known in the art or can be prepared by methods known in the art or in analogy thereto.
- R 1 is as described above and R 2 is lower alkyl, C4_6-cycloalkyl or is a five-or six- membered heteroaryl group, optionally substituted by lower alkyl; Scheme 2
- a compound of general formula la can be obtained by coupling acid V with an amine H 2 N-R1 (step 5). Alternatively, it can be obtained by reaction an amine H 2 N-R1 with acid chloride V (step 7).
- a compound of general formula lb is obtained from a compound of general formula la by Suzuki reaction with a heteroaryl boronic acid or heteroaryl boronic acid ester or alternatively by reaction with dimethyl zinc or cyclopropyl boronic acid in the presence of a Pd catalyst (step 8).
- a compound of general formula Ic is obtained by Suzuki reaction of a benzyl halogenide with a boronic acid ester of general formula VIII (step 11).
- a compound of general formula Id is obtained by reductive amination of an aldehyde X with a substituted piperidine (step 14).
- Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography, thick-layer chromatography, preparative low or high-pressure liquid chromatography or a combination of these procedures.
- suitable separation and isolation procedures can be had by reference to the preparations and examples herein below. However, other equivalent separation or isolation procedures could, of course, also be used.
- the compounds of formula I are basic and may be converted to a corresponding acid addition salt.
- the conversion is accomplished by treatment with at least a stoichiometric amount of an appropriate acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
- an appropriate acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like
- organic acids such as acetic acid, propionic acid, glycolic acid,
- the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol and the like, and the acid added in a similar solvent.
- an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol and the like.
- the temperature is maintained between 0 °C and 50 °C.
- the resulting salt precipitates spontaneously or may be brought out of solution with a less polar solvent.
- the acid addition salts of the basic compounds of formula I may be converted to the corresponding free bases by treatment with at least a stoichiometric equivalent of a suitable base such as sodium or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, and the like.
- a suitable base such as sodium or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, and the like.
- the compounds of formula I and their pharmaceutically usable addition salts possess valuable pharmacological properties. Specifically, it has been found that the compounds of the present invention have an activity as neurogenic agents.
- the assay is designed to select compounds that possess modulator activity at the
- acetylcholine muscarinic receptor expressed in CHO cells by measuring the intracellular calcium with a Fluorometric Imaging Plate Reader System (FLIPR, Molecular Devices).
- FLIPR Fluorometric Imaging Plate Reader System
- the assay study the effect of several concentrations of test compounds on basal or acetylcholine - stimulated Ca 2+ levels using FLIPR.
- BioCoat 96 well black/clear plate (Becton 35 4640). The cells are grown at 37°C and 5% C0 2 in the following medium: F12 Nut Mix (Gibco 21765), 10% FCS heat inactivated (GIBCO 16000-044), 1 % Pen Strep (Gibco,15140) and 200 ⁇ g/ ml Geneticin (Gibco 11811).
- Two minutes preincubation with the diluted test compounds is provide to determine any agonist activity on the Ml receptor by comparison to 30 nM Acetylcholine control.
- the diluted compounds were added to cells and after two minutes preincubation, the EC 2 o of acetylcholine is added followed by another two minutes preincubation before the
- the 26 compounds of formula (I) and pharmaceutically acceptable salts thereof can be used as medicaments, e.g. in the form of pharmaceutical preparations.
- the pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelantine capsules, solutions, emulsions or suspensions.
- the administration can also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
- the compounds of formula (I) and pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations.
- Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelantine capsules.
- Suitable carriers for soft gelantine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelantine capsules.
- Suitable carriers for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like.
- Adjuvants such as alcohols, polyols, glycerol, vegetable oils and the like, can be used for aqueous injection solutions of water-soluble salts of compounds of formula (I), but as a rule are not necessary.
- Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
- the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
- medicaments containing a compound of formula (I) or pharmaceutically acceptable salts thereof and a therapeutically inert excipient are also an object of the present invention, as is a process for the production of such medicaments which comprises bringing one or more compounds of formula (I) or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical dosage form together with one or more therapeutically inert carriers.
- the dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case.
- the effective dosage for oral or parenteral administration is between 0.01-20 mg/kg/day, with a dosage of 0.1-10 mg/ kg/day being preferred for all of the indications described.
- compositions comprising compounds of the invention:
- Step 4 4-r(6-Chloro-3-pyridyl)methyll-l-fluoro-naphthalene-2-carboxylic acid
- Step 1 4-Bromo- l-fluoro-N-(( 3RS,4SR)-3-hvdroxytetrahvdro-2H-pyran-4-yl)-2- naphthamide
- Step 2 l-Fluoro-N-((3RS,4SR)-3-hvdroxytetrahvdro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-2-naphthamide
- the mixture was cooled to room temperature, diluted with ethyl acetate and washed with water. The aqueous layer was back-extracted once with ethyl acetate. The combined organic fractions were dried over Na 2 S0 4 , filtered and concentrated. The crude product was purified by silica gel chromatography using a heptane/EtOAc gradient as eluent to obtain the title compound (240 mg, 79%) as white solid.
- Step 1 Methanesulfonic acid tetrahvdro-pyran-4-yl ester
- the resultant white suspension was diluted with water (250 ml) and then with aqueous solution of Na 2 S0 3 .
- the mixture was stirred at 25°C for 10 min, then basified by addition of saturated aqueous solution of NaHC0 3 .
- the organic layer was separated, and the aqueous layer was re-extracted with CH 2 C1 2 .
- the combined organic layers were washed with saturated aqueous solution of NaHC0 3 (100 ml), and brine (80 ml), dried over anhydrous Na 2 S0 4 , filtered and concentrated in vacuo to afford the title compound (5 g, 70%; crude) as yellow liquid.
- Step 6 (3S, 4R)-3-Hvdroxy-tetrahvdro-pyran-4-yl)-carbamic acid benzyl ester and ((3R, 4S)- 3-hvdroxy-tetrahydro-pyran-4-yl)-carbamic acid benzyl ester
- examples 2 and 3 of the following table were prepared by coupling 4-((6-chloropyridin-3-yl)methyl)-l-fluoro-2-naphthoic acid (example A. l) with an amine.
- Step 1 4-Bromo-l-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-2-naphthamide
- More potassium trifluoro(vinyl)borate (41.7 mg, 311 ⁇ ) was added and the mixture was stirred at 160°C for 30 minutes under microwave irradiation, then diluted with water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over Na 2 S0 4 , filtered and concentrated. The crude product was purified by chromatography on Isolute ® Flash-NH 2 silica gel (from Separtis) using a heptane/EtOAc gradient to obtain the title compound (96 mg, 49%) as off white solid.
- Step 3 l-Fluoro-4-formyl-N-((lS,2S)-2-hydroxycyclohexyl)-2-naphthamide
- the combined organic extract was washed with water and brine, dried over Na 2 S0 4 , filtered and concentrated.
- the crude product was purified by silica gel chromatography using a heptane/EtOAc gradient as eluent to obtain the title compound (11 mg, 56%) as white solid.
- Step 4 4-((4-Cyano-4-(pyridin-2-yl)piperidin-l-yl)methyl)-l-fluoro-N-((lS,2S)-2-hydroxy- cyclohexyl)-2-naphthamide
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EP15702398.7A EP3097094B1 (de) | 2014-01-22 | 2015-01-19 | Fluor-naphthyl-derivate |
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EP14152124 | 2014-01-22 | ||
EP15702398.7A EP3097094B1 (de) | 2014-01-22 | 2015-01-19 | Fluor-naphthyl-derivate |
PCT/EP2015/050830 WO2015110370A1 (en) | 2014-01-22 | 2015-01-19 | Fluoro-naphthyl derivatives |
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CN (1) | CN105793259A (de) |
CA (1) | CA2930961A1 (de) |
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CN109069491A (zh) | 2016-02-16 | 2018-12-21 | 范德比尔特大学 | 毒蕈碱型乙酰胆碱受体m1的正向别构调节剂 |
JP6860551B2 (ja) | 2016-03-11 | 2021-04-14 | 武田薬品工業株式会社 | 芳香環化合物 |
JP6629486B2 (ja) | 2016-09-02 | 2020-01-15 | スヴェン・ライフ・サイエンシズ・リミテッド | ムスカリンm1受容体陽性アロステリックモジュレーター |
WO2018063552A1 (en) | 2016-09-30 | 2018-04-05 | Vanderbilt University | Positive allosteric modulators of the muscarinic acetylcholine receptor m1 |
EA035599B1 (ru) * | 2017-04-13 | 2020-07-14 | Сувен Лайф Сайенсиз Лимитед | Позитивные аллостерические модуляторы мускариновых m1-рецепторов |
JP7197472B2 (ja) * | 2017-05-19 | 2022-12-27 | 武田薬品工業株式会社 | スクリーニング方法 |
EP3700895B1 (de) * | 2017-10-27 | 2021-09-22 | Suven Life Sciences Limited | Polycyclische amide als muscarin-m1-rezeptor-positive allosterische modulatoren |
AU2019362468B2 (en) | 2018-10-17 | 2022-04-21 | Suven Life Sciences Limited | Pyrrolo-pyridazine derivatives as muscarinic M1 receptor positive allosteric modulators |
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RU2016132858A (ru) | 2018-03-02 |
CA2930961A1 (en) | 2015-07-30 |
EP3097094B1 (de) | 2020-01-15 |
MX2016008536A (es) | 2016-09-26 |
KR20160098500A (ko) | 2016-08-18 |
CN105793259A (zh) | 2016-07-20 |
US9708302B2 (en) | 2017-07-18 |
JP2017501233A (ja) | 2017-01-12 |
US20160326144A1 (en) | 2016-11-10 |
WO2015110370A1 (en) | 2015-07-30 |
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